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CIRCUITOS
INTEGRADOS EN
CANCER
METABOLISMO Y CÁNCER
METABOLISMO ENERGETICO
DEREGULADO
Glucosa, insulina,
metabolismo y cáncer
La insulina es un factor de
crecimiento
BANTING Y BEST (TORONTO, 1921)
BANTING Y MACLEOD, PREMIO NOBEL DE MEDICINA, 1923
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GLUT 4
GLUT 4
Tyrosine kinase receptors, including the insulin receptor, mediate their activity by causing the addition of a phosphate group
to particular tyrosine residues on certain proteins within a cell. The "substrate" proteins that are phosphorylated by the Insulin
receptor include a protein called "IRS-1" for "insulin receptor substrate 1".
IRS 1 binding and phosphorylation eventually leads to an increase in the high affinity GLUT4 (Glucose transporter 4)
molecules on the outer membrane of insulin-responsive tissues, including Myocytes and Adipocytes. Thus there is an increase
in the uptake of Glucose molecules from blood into these cells. The glucose transporter GLUT4 is transported from cellular
vesicles to the cell surface, where it then can mediate the transport of glucose into the cell.
GLUCOSA
ACIDO
PIRUVICO
ACIDO LACTICO
CICLO DE KREBS
VISTA GENERAL Y GLOBAL DE LA PRODUCCION DE ENERGIA
LACTATO
SE CONSUMEN 2 ATPs
SE PRODUCEN 4 ATPs
BALANCE NETO 2 ATPs
El ciclo de Krebs y la cadena
respiratoria producen 36 ATPs
La cadena de transporte de
electrones
La cadena de transporte de
electrones
2 H+ + 2 e + 1/2 O2 ---> H2O + energy
BALANCE ENERGETICO
• El efecto Warburg
Otto Warburg. Premio Nobel de Fisiología 1931
IMAGEN DE CEREBRO EN PET SCAN
PET SCAN DE LINFOMA ANTES Y DESPUES TRATAMIENTO (FDG)
Figure 1. The Altered Metabolism of Cancer Cells Drivers (A and B). The
metabolic derangements in cancer cells may arise either from the selection
of cells that have adapted to the tumor microenvironment or from aberrant
signaling due to oncogene activation. The tumor microenvironment is
spatially and temporally heterogeneous, containing regions of low oxygen
and low pH (purple). Moreover, many canonical cancer-associated signaling
pathways induce metabolic reprogramming. Target genes activated by
hypoxia-inducible factor (HIF) decrease the dependence of the cell on
oxygen, whereas Ras, Myc, and Akt can also upregulate glucose
consumption and glycolysis. Loss of p53 may also recapitulate the features
of the Warburg effect, that is, the uncoupling of glycolysis from oxygen
levels.Advantages (C–E). The altered metabolism of cancer cells is likely to
imbue them with several proliferative and survival advantages, such as
enabling cancer cells to execute the biosynthesis of macromolecules (C), to
avoid apoptosis (D), and to engage in local metabolite-based paracrine and
autocrine signaling (E).Potential Liabilities (F and G). This altered
metabolism, however, may also confer several vulnerabilities on cancer
cells. For example, an upregulated metabolism may result in the build up of
toxic metabolites, including lactate and noncanonical nucleotides, which
must be disposed of (F). Moreover, cancer cells may also exhibit a high
energetic demand, for which they must either increase flux through normal
ATP-generating processes, or else rely on an increased diversity of fuel
sources (G).
Glucose metabolism in cancer
¿El cáncer es tonto?
– ¿Porqué una célula tumoral, que tiene
grandes requerimientos de energía prioriza la
vía de la glucólisis aerobia que solo produce 2
ATPs, en lugar de la vía de la fosforilación
oxidativa que produce 36 ATPs?
Ensayaremos una respuesta
• El cáncer no es tonto.
• Además de energía, la célula tumoral requiere
•
•
también muchas otras sustancias para elaborar
ácidos grasos, proteínas y ribosa fosforilada.
Estas sustancias se elaboran a partir del ácido
láctico, excepto la ribosa.
Por otro lado, no se produce déficit energético
porque la célula tumoral metaboliza 10 veces
más moléculas de glucosa en la unidad de
tiempo que la célula no tumoral.
El Efecto Warburg es mal entendido
M. G. Vander Heiden et al. addressed the question of why a cell would "choose"
glycolysis over oxidative phosphorylation, whereby only 2 instead of 36 adenosine
5'-triphosphate (ATP) are obtained per glucose molecule ("Understanding the
Warburg Effect: The metabolic requirements of cell proliferation," Reviews, 22
May 2009, p. 1029). However, the question, as well as the proffered explanations,
misses the point of Warburg's work. In 1923 and 1924, Warburg and co-workers
reported that the rate of respiration in cancer cells is, within the error, identical to
that of normal cells, and that the glucose uptake is approximately 10 times
higher. Furthermore, for every 13 glucose molecules taken up, 1 is oxidized via
respiration, while the remaining 12 are split to form lactic acid (1, 2). Thus, in the
time that one glucose molecule produces 36 ATP via respiration, 24 additional
ATP are generated via aerobic glycolysis. The question posed by Vander Heiden et
al., "why do proliferating cells switch to a less efficient metabolism" is wrong on
two counts: (i) cancer cells do not switch, but carry out both oxidative
phosphorylation and aerobic glycolysis simultaneously, and (ii) glycolysis is not
inefficient; even in the absence of oxygen, cancer cells survive because lactic acid
production via anaerobic glycolysis yields 2/3 of the ATP that a normal cell
produces by respiration. Indeed, it is precisely this enormous uptake of glucose
that allows cancerous tissue to be visualized by FDG-PET/CT.
The question of whether or not cancer cells respire normally has dogged the
literature since the late 1920s. Experimental results of Warburg and co-workers
and of Chance and co-workers (3, 4) clearly show that respiration is normal. Why
then did Warburg himself in 1956 write that "…the respiration of all cancer cells
is damaged..." (5)? Warburg later provided clarification that has largely gone
unnoticed, writing that the respiration of cancer cells is small relative to the
consumption of glucose, but not small relative to the respiration of normal cells
(6). The confusion may have been prevented had Warburg formulated his
definition of respiratory impairment 30 years earlier.
Willem H. Koppenol and Patricia L. Bounds Institute of Inorganic Chemistry, Department of Chemistry and Applied Biosciences, ETH,
Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland.
¿Qué o quien genera el efecto Warburg
(fenotipo de glucólisis aerobia)?
• 1) Alteraciones en la señalización de p53, myc,
•
•
•
•
•
ras, akt y HIF-I
2) Papel de la piruvato kinasa
3) Hipoxia del medio ambiente tumoral
4) Mutaciones del gen de von Hippel Lindau
5) Mutaciones del gen de la succinato
dehidrogenasa y/o gen de la fumarasa.
6) Alteración del equilibrio VDAC-HK-II
(potencial de membrana del poro mitocondrial y
hexosakinasa-II)
All cancer cells but not nontransformed cells express a specific splice variant of pyruvate kinase,
termed M2-PK, that is less active, leading to the build up of phosphoenolpyruvate. Recent work has
revealed that reduced activity of M2-PK promotes a unique glycolytic pathway in which
phosphoenolpyruvate is converted to pyruvate by a histidine-dependent phosphorylation of
phosphoglycerate mutase, promoting assimilation of glycolytic products into biomass
Bibliografia
• Vamecq J, Colet JM et all
PPARs: Interference with Warburg effect and clinical anticancer trials.
PPAR Research Vol 2012 doi 10.1155/2012/304760
• Vander Heiden MG, Cantley LC,* and Thompson CB
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Science 22 May 2009: Vol. 324 no. 5930 pp. 1029-1033 DOI: 10.1126/science.1160809
• Bensinger SJ, Christofk HR
New aspects of the Warburg effect in cancer cell biology.
Semin Cell Dev Biol. 2012 Jun;23(4):352-61
• Najafov A, Alessi DR
Uncoupling the Warburg effect from Cancer
PNAS (2010) 107:19135-19136
History of HIF research
• Clone the Erythropoietin gene(1985)
• Erythropoietin induced by hypoxia(1987)
• Discovery of hypoxic inducible nuclear factor
•
•
•
•
binding to enhancer of EPO gene
named as
HIF-1(Semenza GL 1992)
HIF-1 activity in cell not expressing EPO during
hypoxia (1993)
HIF-1 is upstream to VEGF-A…etc.
VHL bind to HIF-1 (1999)
Growth factor and AKT upstream HIF-1(1999)
HIF-1
• A heterodimeric member of basic helix-loop-helix
•
•
•
(bHLH) family, containing PAS domain
Compose HIF-1 α and HIF-1β
Persistent expression of HIF-1 β, identical to aryl
hydrocarbon receptor(AHR) nuclear translocator
(ARNT)
Binding to DNA sequence 5’-(A/G)CGTG-3’(HRE)
Trends Cardiovasc med 1996;6:151-7
RAS
Raf
MEK
ERK
?
Overview
HIF-1 signal
pathway
CCR 2003;9:4641-52
modified
La sorpresa: simbiosis metabólica
• Los tumores se componen de dos tipos
celulares:
• A) Células normóxicas que metabolizan
glucosa y ácido lactico
• B) Células hipóxicas que producen ácido
láctico a partir de glucosa
El ácido láctico producido por las células hipóxicas es
incorporado por las células normóxicas y utilizado para
elaborar energía y otros productos
La enzima clave para este proceso es MCT1
(monocarboxilate transporter1)
Sonveaux et al. The Journal of Clinical Investigation 2008 Vol 118(12): 3930-3941
Symbiotic
Metabolic
Process